Process for preparing 1-(dihydroxy-phenyl)-2-amino butanol-1 and intermediates



Patented Nov. 18, 1947 PROCESS FOR PREPARING 1- (DIHYDROXY- PHENYL)-2-AMINO BUTANOL-l AND IN- TERIHEDIATES Chester Merle' Suter and Arlo Wayne Ruddy, Albany. N. Y., assignors, by mesne assignments, to Winthrop-Stearns Inc., New York, N. Y., a corporation of Delaware RElSSUED APR 19 1949 No Drawing. Application March 16, 1944, Serial No. 526,809

16 (llaims. (Cl. 260-570.!

This invention relates to therapeutic agents having a vasoconstrictor action, intermediates useful in the production thereof and to improved methods for their preparation.

economically by reacting a compound newly discovered by us and having the formula It has been found that the compound having 5 the formula R 0 0E (ll-CHC:H|

m where R and R" are arylmethyl, and X is a middle halogen, i. e., chlorine or bromine, with a pri- H mary amine having the formula RNH2, where and known fihemically as 3, y 0 y- R is diarylmethyl, and hydrogenating the result- P e y -a has especially ing (diarylmethyD-amino ketone or an acid advantageous P operties which make it a peculiarly dition salt thereof in the presence of anoble useful vasoconstrictor agent. In particular, it is metal, preferably palladium, catalyst. equally as effective as epinephrine in the relief We prefer to conduct our new process by heatof acute asthmatic attacks in doses larger and ing a-bromo-3,4-dibenzyloxybutyrophenone with the relief is accompanied by fewer side-effects. 2o benzhydrylamine. The resulting a-benzhydryl- This compound is approximately only as toxic amino-3,4 dibenzyloxybutyrophenone is conas epinephrine. The compound enjoys the verted into an acid addition salt such as the unique and especially valuable property of exerthydrochloride, by treating the free base with the ing its action without exciting the central nervous requisite amount of acid. This salt is dissolved system nor raising the systolic blood pressure. in a suitable solvent such as alcohol and hy- Instead, it lowers the diastolic blood pressure and drogenated in the presence of a palladium catincreases the pulse rate, thus improving circulaalyst. After three moles of hydrogen are abtion without a proportionate rise in cardiac work. sorbed, the product, a-amino-3A-dihydroxy- These highly desirable properties are enjoyed not butyrophenone can be isolated. On further hycnly by the compound l-(3,4-dihydroxyphenyl)- drogenation, this is reduced to 1-(3,4-d ihydroxy- 2-amino-1-butanol itself, that is in the form of phenyl)-2-amino-l-butanol. Thus the two the free base, but also in the form of its acid adbenzyl groups and the benzhydryl group are redition salts. Such acid addition salts include the moved by hydrogenolysis, while the ketone group hydrochloride, the sulfate, the tartrate, and in is reduced to the desired hydroxyl group. In this general all of its other salts with acids which connection it must be observed that l-(3,4-dihyare themselves non-toxic to the organism in droxyphenyl) -2-amino-l-butanol is theoretically dosages correspdnding to the therapeutic dose capable of existing in two racemic forms since of the amine salt. the carbon atoms numbered 1 and 2 in the above We have set ourselves to the problem of deformula are both asymmetric and different. It is veloping a satisfactory procedure by which this 40 quite surprising that only one kind of racemate drug may be manufactured and made available is formed according to our new process and that to the medical profession. In searching for suitthis racemate is the one desired and having the able means of obtaining this amine, the usual favorable physiological and therapeutic propmethods for preparing arylalkanolamines proved erties. to be unsatisfactory. Our invention also contemplates new inter- Now we have found, however, that the-compound or its salts can be prepared readily and mediates especially useful for the preparation of 1-(3,4-dihydroxyphenyl) -2- amino -1- butanol.

onaco 3 These intermediates are aminoketones having the formula o-cn-om lowing example, but without being restricted' thereto.

(a) 3,4-dihydron/butw'ophenone To 165 gm. of catechol in 660 cc. of dry chlorobenzene is added 200 gm. of n-butyryl chloride, and the mixture heated at 50 C. for 30 minutes. It is then cooled and 426 gm. oi anhydrous aluminum chloride is added in small portions. Then the temperature of the mixture is gradually raised to 100 C. and held there ior 3 hours. The mixture is hydrolyzed by pouring it onto ice and hydrochloric acid, and, the chlorobenzene removed by steam distillation. While the mixture is still warm, 75 cc. of concentrated hydrochloric acid and 125 cc. oi toluene are added. After thorough cooling, the deposited solid is collected by filtration and washed well with water and toluene. After recrystallization from water, this product, 3,4-dihydroxybutyrophenone, melts at 146 l46.5 C.

(b) 3,4-dibenzylorvbutvrophenone A mixture of 184.5 gm. of 3,4-dihydroxybutyrophenone, 278.5 gm. of benzyl chloride, 187 gm. of anhydrous potassium carbonate, 13.5 gm. of sodium iodide in 500 cc. of alcohol and 8 cc. of water is refluxed and stirred for hours when all efiervescence has ceased. The alcohol is distilled oil and any unreacted benzyl chloride removed by steam distillation. The warm mixture is poured into dilute sodium hydroxide, cooled, filtered, and washed with water until neutral to litmus. Recrystallization from alcohol gives a 90% yield of 3,4-dibenzyloxybutyrophenone. M. P. 86-87 C.

(c) a-Bromo-3,4-dibenzyloa:ybutrophenone To 335.5 gm. of 3,4-dibenzyloxybutyrophenone dissolved in 1500 cc. of methylene chloride is added 110 gm. of powdered calcium carbonate and then 149 gm. of brominedn 400 cc. of methylene chloride. The excess calcium carbonate is dissolved with dilute hydrochloric acid, the methylene chloride layer separated, washed with water, and dried over sodium sulfate. After removing the solvent under reduced pressure, the residue is recrystallized from alcohol. A 70% yield of cream-colored crystals, M. P. 100-101" C., is obtained.

(d) a Benzhydrylamino-3,4-dibenzylo:cybutyrophenone hydrochloride To 57.1 gm. of a-bromo-3,4-dibenzyloxybutyrophenone in 175 cc. of absolute alcohol is added 47.7 gm. of benzhydrylamine and the mixture refluxed three hours. The alcohol is completely removed under reduced pressure and 400 cc. of

moved by extracting with ether.

solution is boneblacked and further hydrogenated until the fourth'equivalent 01' hydrogen has and thoroughly shaken with dry ether added. Thepreclpitated benzhydryl amine bydrobrotnide is filtered and washed with dry ether. The ether solutions are combined hydrochloric acid. An oil separates and crystallizes slowly. It is filtered oil, washed with water and with ether to remove traces of color. A 75% yield oi cream-colored needles, M. P. 175-176 6., with decomposition, is obtained.-

(c) i-(aA-dihydroxybhehill)-2-dmino-1-butanol hildrochloride- To 28.9 gm. oi a-benzhydrylamino-3,4-dibenzyloxybutyrophenone. dissolved in 150 cc. of absolute alcohol, is added 0.5 gm. of palladium catalyst, prepared according to the method 01 .Willstatter and Waldschmidt-Ieitz (Berichte 54,

123, 1921). The mixture is shaken at 55-70 C. under fii'ty pounds pressure until three equivalents of hydrogen have been used. After the alcohol is removed, the residue is dissolved in water and the toluene and diphenylmethane rebeen used. 7 The catalyst is removed and the solution taken to dryness under reduced pressure. The residue is boneblacked in absolute alcohol, an equal volume of acetone added and then dry ether added until precipitation is complete. A

'60% yield of colorless material is obtained.

When completely dry it melts with decomposition at 199-200 C.

When the hydrogenation is interrupted after the absorption of three moles of hydrogen and the reaction mixture worked up at this point. by evaporating the alcohol, dissolving the residue in water, and rendering the aqueous solution alkaline by addition of aqueous ammonia, 4:- amino (3,4-dihydroxyphenyl) -butyrophenone is obtained. It melts at 187-188 C., with decomposition, and forms a. hydrochloride melting at approximately 178-179 C., with decomposition. This salt, and other acid addition salts, can be prepared by adding the requisite acid to an alcoholic suspension of the base, and isolating the salt by evaporation or by precipitation with ether.

It will be appreciated that our invention is subject to numerous variations with regard to the particular details involved in the various steps. For example, instead oi. using benzyl groups to protect the phenolic hydroxyl groups during halogenation, we can employ other protecting arylmethyl groups such as p-chlorobenzyl, p-methoxybenzyl, p-methylbenzyl, or the like.

Similarly, instead of using benzhydrylamine as the ,-diarylmethylamine, we can use derivatives of benzhydrylamine in which one or both benzene rings are substituted by unreactive groups such as halogen, alkyl or alkoxyl.

However, the use of substituted benzyl, and substituted benzhydryl compounds usually oflers no advantage, and in practice we prefer to use th cheaper, ring-unsubstituted compounds.

Likewise, instead of using a bromoketone. we

can also employ the corresponding chloroketone. In the appended claims we employ the term middle halogen to include both bromine and chlorine.

The noble metal catalyst can be any metal of the platinum group. We prefer palladium because it is cheaper than platinum, and afl'ords a clean-cut hydrogenation, in contrast to some instances where we have found the hydrogenation difflcult to control, when using platinum.

some

The aqueous Because of these permissible variations we do not limit the scope of our invention to the specific forms shown. Rather, the scope is defined by the subjoined claims.

What we claim is:

1. The process which comprises reacting a compound having the formula where R and R are arylmethyl and X is a middle halogen, with an amine having the formula RNH2, where R is a diarylmethyl, and hydrogenating the resulting a-[(diarylmethyl)- aminol-ketone or an acid addition salt thereof in the presence of a noble metal catalyst, thereby p in a derivative of 1-(3,4-dihydroxyphenyl) -2-amino-1-butanol, or an acid addition salt thereof.

2. A process according to claim 1 where the noble metal catalyst is palladium.

3. A process according to claim 1 where the amine of formula R'-NH2 is benzhydrylamine.

4. The process which comprises reacting abromo-3,4-dibenzyloxybutyrophenone with benzhydrylamine, forming an acid addition salt of the resulting a-benzhydrylamino-3,4-dibenzyloxy-butyrophenone by reacting the latter with an acid,

and hydrogenating the resulting acid addition salt of a-benzhydrylamino-3A-dibenzyloxybutyrophenone in the presence of a noble metal catalyst, thereby producing an acid addition salt of 143,4- dihydroxyphenyl) -2-amino-1-butanol.

5. The process which comprises reacting abromo-3,4-dibenzyloxybutyrophenone with benzhydrylamine, forming the hydrochloride of the resulting a-benzhydrylamino 3,4 dibenzylcxybutyrophenone by reacting the latter with hydrohloric acid, and hydrogenating the resulting hydrochloride of w-benzhydrylamino-3,4-dibenzyloxybutyrophenone in the presence of a palladium catalyst, thereby producing the hydrochloride of 1- (3,4-dihydroxyphenyl) -2-amino-1-butanol.

6. In a process for producing 1-(3,4-dihydroxyphenyl) -2-amino-1-butanol and its acid addition salts, the step which comprises reacting a compound having the formula -0 H-CIHI where R and R" are arylmethyl and X is a middle halogen, with an amine having the formula R-NHz, where R is a diarylmethyl.

7. In a process for producing 1-(3,4-dihydroxyphenyl-2-amino-1-butanol and its acid addition salts, the step which comprises reacting a-bromo- 3,4-dibenzyloxybutyrophenone with benzhydrylamine.

8. In a process for producing 1-(3,4-dihydroxyphenyl) -2-amino'-l-butanol and its acid addition salts, the step which comprises hydrogenating, in the presence of a noble metal catalyst, a member of the class consisting of a, compound having the formula where R is a member of the group consisting of O-CH- C|Hs r ma whereR' and R" are arylmethyl, and R is diarylmethyl, and acid addition salts of said compound.

9. A process according to claim 8 wherein the noble metal catalyst is palladium.

10. In a process for producing l-(3,4-dihydroxyphenyl-2-amino-1-butanol and its acid addition salts, the step which comprises hydrogenating abenzhydrylamino -3,4- dibenzyloxybutyrophenone in the presence of a palladium catalyst.

11. A compound having the formula C-OH-C 1H0 NHR hydrogen and diarylmethyl and R' and R" are members of the group consisting of hydrogen and arylmethyl, and the acid addition salts of said aminoketones.

12. A compound having the formula mm where R is diarylmethyi and R and R" are arylmethyl.

13. a Benzhydrylamino- 3,4- dibenzyloxybutyrophenone, having the formula 0-benzyl benzyl-O C-GH-CaHs NH-benzhydryl and forming a hydrochloride melting at approximately -176 0., with decomposition.

14. -Amino-3,4-dihydroxybutyrophenone, having the formula and melting at approximately 187-188 C. with decomposition.

15. An acid addition salt of a-amino-SA-dihydroxy-butyrophenone.

16. a-Amino-8,4-dihydroxybutyrophenone hy-' drochloride, melting at approximately 178-179 C. with decomposition.

CHESTERMERLESUTER. ARLO WAYNE BUDDY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Bockmuhl I May 1, 1934 Bockmuhl II June 8, 1937 Number 

